title: An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway.
abstract: Misregulated β-catenin responsive transcription (CRT) has been implicated in the genesis of various malignancies, including colorectal carcinomas, and it is a key therapeutic target in combating various cancers. Despite significant effort, successful clinical implementation of CRT inhibitory therapeutics remains a challenging goal. This is, in part, because of the challenge of identifying inhibitory compounds that specifically modulate the nuclear transcriptional activity of β-catenin while not affecting its cytoskeletal function in stabilizing adherens junctions at the cell membrane. Here, we report an RNAi-based modifier screening strategy for the identification of CRT inhibitors. Our data provide support for the specificity of these inhibitory compounds in antagonizing the transcriptional function of nuclear β-catenin. We show that these inhibitors efficiently block Wnt/β-catenin-induced target genes and phenotypes in various mammalian and cancer cell lines. Importantly, these Wnt inhibitors are specifically cytotoxic to human colon tumor biopsy cultures as well as colon cancer cell lines that exhibit deregulated Wnt signaling.
authors.affiliation: Department of Pharmacology and New York University Cancer Institute, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Foster C
authors.initials: FC
authors.lastname: Gonsalves
authors.forename: Keren
authors.initials: K
authors.lastname: Klein
authors.forename: Brittany B
authors.initials: BB
authors.lastname: Carson
authors.forename: Shauna
authors.initials: S
authors.lastname: Katz
authors.forename: Laura A
authors.initials: LA
authors.lastname: Ekas
authors.forename: Steve
authors.initials: S
authors.lastname: Evans
authors.forename: Robert
authors.initials: R
authors.lastname: Nagourney
authors.forename: Timothy
authors.initials: T
authors.lastname: Cardozo
authors.forename: Anthony M C
authors.initials: AM
authors.lastname: Brown
authors.forename: Ramanuj
authors.initials: R
authors.lastname: DasGupta
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D004331:Drosophila melanogaster; D055808:Drug Discovery / Q000379:methods*; D004354:Drug Screening Assays, Antitumor; D017930:Genes, Reporter; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D010080:Oxazoles / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use; D034622:RNA Interference; D054852:Small Molecule Libraries; D014158:Transcription, Genetic / Q000187:drug effects*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D051155:Wnt1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D029721:Drosophila Proteins; D010080:Oxazoles; D054852:Small Molecule Libraries; D051153:Wnt Proteins; D051155:Wnt1 Protein; D051176:beta Catenin; C000604582:iCRT3 compound; C074622:wg protein, Drosophila